Benign hyperproliferative disorders of the skin result from excess keratin deposition (hyperkeratosis) of the corneous layer. Such hyperproliferative disorders include epidermolytic hyperkeratosis and follicular keratosis. One common benign hyperproliferative disorder is hypertrophic scar formation (a keloid), a sharply elevated, irregularly-shaped, progressively enlarging scar due to the formation of excessive amounts of collagen in the corium during connective tissue repair following surgical and traumatic lacerations. While such hypertrophic tissue repair is most evident at sites of external wound healing, keloid-prone individuals also manifest hypertrophic scarring internally. The major consequences of external keloid scarring are mainly cosmetic, although keloids can also result in varying degrees of psychological and social trauma for the afflicted individuals. In such cases, surgical or laser intervention is indicated because there is currently no generally effective topical or systemic treatment for this condition. Other hyperproliferative disorders are corns and calluses. Current non-surgical treatments for less acute cases of hyperkeratosis include 17% salicylic acid in collodion and 40% salicylic acid plasters. A keloid is usually treated by injection of a corticosteroid into the base of the lesion. This treatment may flatten the keloid, but is often ineffective.
Malignant hyperproliferative disorders of the skin include Kaposi's sarcoma (KS) and skin cancer. KS is a neoplasm, often associated with AIDS patients, characterized by vascular skin tumors. KS lesions originate from multifocal sites in the mid-dermis and extend to the epidermis. Histopathology shows spindle cells and vascular structures admixed to various degrees. Repeated biopsies show a progressive sarcomatous-like appearance. In more advanced stages, the lesions appear as multiple purplish to brown subcutaneous nodular or plaque-like dermal lesions, often with a varicose surface. The characteristic histological features of KS include the proliferation of spindle-shaped cells (KS cells, considered the tumor element) and of endothelial cells (CDC Task Force on KS and Opportunistic Infections, New Engl. J. Med., 306:248, 1982). There are two types of KS: indolent and lymphadenopathic. Indolent KS is characterized by nodular or plaque-like dermal lesions. Treatment options include freezing, electrocoagulation or electron beam radiotherapy. Unresponsive lesions are treated locally with 1,000-2,000 rads of x-ray therapy.
Aliphatic alcohols are known to have various biological activities. U.S. Pat. No. 3,031,376 discloses that n-tetracosanol (C24), n-hexacosanol (C26), n-octacosanol (C28) and triacontanol (C30) and their esters improved physical performance of athletes and disclosed compositions comprising such alcohols and esters for oral ingestion. U.S. Pat. No. 4,670,471 discloses the use of triacontanol for treatment of inflammatory disorders such as herpes simplex, eczema, shingles, atopic dermatitis and psoriasis. U.S. Pat. No. 3,592,930 discloses a medicant vehicle comprising 15 to 45 parts of saturated aliphatic alcohol having from 16 to 24 carbons as a carrier for antibiotics, steroids and antihistamines. U.S. Pat. No. 3,863,633 discloses a composition for topical treatment of the eye comprising 10-80% C12 to C22 surface active alcohols such as n-docosanol, n-hexadecanol, n-octadecanol and n-eicosanol. U.S. Pat. No. 4,874,794 discloses a method of treating virus-induced and inflammatory diseases of the skin and membranes with a composition comprising one or more of the aliphatic alcohols n-docosanol (C22), n-tetracosanol and n-hexacosanol. Antiviral and anti-inflammatory activities of aliphatic alcohols having from 20 to 32 carbons are disclosed in U.S. Pat. No. 4,874,794, U.S. Pat. No. 5,071,879, U.S. Pat. No. 5,166,219, U.S. Pat. No. 5,194,451 and U.S. Pat. No. 5,534,554. Related chemical compounds and compositions having therapeutic activities are disclosed therein.
A C22 aliphatic alcohol, n-docosanol, suspended in a surfactant exhibits potent antiviral activity against a variety of lipid enveloped viruses including herpes simplex virus and respiratory syncytial virus in cell culture assays (Katz, D. H., et al., Proc. Natl. Acad. Sci. USA 88:10825-10829, 1991; U.S. Pat. No.5,534,554, hereby incorporated by reference). Intracellular metabolic conversions of n-docosanol may account for its antiviral activity (Pope et al., J. Lipid Res., 37:2167-2178, 1996). The alcohol is not cytotoxic in concentrations up to 300 mM.
There is a need for therapeutic agents which will inhibit hyperproliferative skin lesions. The present invention addresses this need.